RNA protein interactions regulate vital biological processes such as transcription and translation and are prominent in the life cycle of retroviruses during propagation, replication, and virion assembly. The interaction between the HIV Tat transactivator protein and its RNA recognition element TAR is of particular interest as a possible target for antiviral drug development, as well as providing a good model for RNA binding in general. Small, soluble synthetic ligands that disrupt Tat binding to TAR will consequently inhibit HIV replication, thus presenting great immediate therapeutic value, and will allow detailed structure-function studies applicable to a wide range of RNA interactions. It is now apparent that small ligands with positively charged backbones are able to bind tightly, if nonspecifically, in the deep, narrow major groove of an A-form helix (the predominant form of an RNA duplex). The synthesis of molecules with a positively charged backbone to provide affinity for the RNA, and side chains to provide specificity for a particular RNA target, may represent a novel class of RNA-binding ligands with both pharmaceutical and pharmacological applications. Synthesis of large combinatorial libraries of these compounds would provide ligands for the study of other RNA interactions that depend on similar charge-charge relationships, as well as a source of possible inhibitors of other biologically relevant interactions. These libraries will be rapidly screened to evaluate the ability inhibit Tat-TAR interaction using an assay based on fluorescence anisotropy.